Is Psilocybin as Effective for Depression as We Think?
Psilocybin trials may overestimate effects due to weak control group response, new meta-analysis finds.
Psilocybin has shown promise as a treatment for depression; however, new research suggests we may be overestimating its impact.
Conducted by researchers in Scandinavia and published in JAMA Network Open, the meta-analysis found that control groups in psilocybin trials improved far less than those in trials of selective serotonin reuptake inhibitors (SSRIs) or esketamine, potentially inflating the drug’s perceived effectiveness.
How psilocybin became a leading antidepressant candidate
Psilocybin – the hallucinogenic ingredient in magic mushrooms – has shown fast, powerful antidepressant effects in clinical trials. Early studies have reported that its impact was more than twice that of standard treatments such as SSRIs. That has driven a wave of optimism about psychedelics as a new class of mental health treatments, especially for people who haven’t responded to existing options.
However, some researchers have started to ask whether the results are too good to be true. A key concern is how these trials are run. Psilocybin’s psychoactive effects are hard to miss, which makes it difficult to properly blind participants and researchers. People often know whether they’ve received the real drug, which could influence outcomes through expectancy bias – if participants expect to feel better, they might report that they do.
In drug trials, participants who receive a placebo or other control treatment usually see some improvement, too. These effects, sometimes quite large, help researchers separate true drug benefits from psychological effects such as expectation. However, control groups in psilocybin trials may not behave like those in other studies, potentially skewing their perceived versus actual beneficial effects.
The new meta-analysis compared control group outcomes across 17 double-blind, randomized clinical trials of psilocybin, SSRIs and esketamine.
Esketamine
Esketamine is a fast-acting antidepressant derived from ketamine. It’s typically administered in nasal spray form and is approved for treatment-resistant depression
New study compares psilocybin to SSRIs and esketamine
The analysis included 4 studies on psilocybin (373 participants), 2 on esketamine (573 participants) and 11 on SSRIs (4014 participants). All focused on adults with major depressive disorder or treatment-resistant depression. Every study used the same tool to track symptoms: the Montgomery–Åsberg Depression Rating Scale, which scores depression severity from 0–60.
The team used two standard metrics: Standardized Mean Change (SMC), which captures how much symptoms changed in each group from before to after treatment, and Standardized Mean Difference (SMD), which compares the effect of the active treatment against the control within the same trial.
“Participants receiving control treatment in psilocybin trials had significantly less improvement in depression ratings than participants receiving control treatment in trials of SSRIs or esketamine,” said the authors.
The average SMC was 0.50 for the psilocybin control arms, compared to 1.00 in the SSRI trials and 1.12 in the esketamine trials, indicating that those not receiving the drug improved much less in the psilocybin studies.
As a result, psilocybin showed a bigger treatment effect – SMD of 0.70, compared to 0.30 for esketamine and 0.27 for SSRIs. However, these results are not down to psilocybin working better, but rather, because its control group didn’t improve as much.
Dropout rates were relatively low in psilocybin control groups (11%), similar to esketamine and much lower than SSRIs. However, response rates were also lowest: only 19% improved in psilocybin controls, vs 33% (SSRIs) and 42% (esketamine).
What psilocybin trials need to improve going forward
The headline finding of this study isn’t that psilocybin doesn’t work, but that it might not work as well as some early results suggest. The big treatment effects seen in psilocybin trials may be exaggerated, creating an uneven comparison.
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If psilocybin trials consistently have weaker-performing control groups, then any head-to-head with SSRIs or esketamine could make psilocybin look better than it is.
“The low response to control treatment suggests that psilocybin may not be as broadly effective for depression as estimated,” said the authors.
The meta-analysis cannot explain why the control groups performed poorly, and currently, there are still only a small number of clinical trials investigating the efficacy of psilocybin.
“Future studies should strive toward a better understanding of which factors moderate control treatment outcomes in psilocybin trials, such as by trialing multiple control treatments and/or by recruiting study participants with positive expectations of the control treatment also,” the authors concluded.
Reference: Hieronymus F, López E, Sjögren HW, Lundberg J. Control group outcomes in trials of psilocybin, SSRIs, or esketamine for depression. JAMA Netw Open. 2025. doi: 10.1001/jamanetworkopen.2025.24119
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